S165: CONTINUOUS TRANFUSION INDEPENDENCE WITH IMETELSTAT IN HEAVILY TRANSFUSED NON-DEL(5Q) LOWER-RISK MYELODYSPLASTIC SYNDROMES RELAPSED/REFRACTORY TO ERYTHROPOIESIS STIMULATING AGENTS IN IMERGE PHASE 3
Authors: Uwe Platzbecker, Valeria Santini, Pierre Fenaux, Mikkael Sekeres, Michael Robert Savona, Yazan Madanat, María Díez Campelo, David Valcárcel, Thomas Illmer, Anna Jonášová, Petra Belohlavkova, Laurie Sherman, Tymara Berry, Souria Dougherty, Sheetal Shah, Qi Xia, Lixian Peng, Libo Sun, Ying Wan, Fei Huang, Annat Ikin, Shyamala Navada, Rami S. Komrokji, Amer M. Zeidan
Journal: HemaSphere (2023)

Background: Unmet need remains for novel therapies after failure of erythropoiesis stimulating agents (ESAs) in red blood cell (RBC) transfusion dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). In IMerge Phase 2 (NCT02598661), treatment with imetelstat, a telomerase inhibitor, resulted in prolonged, durable transfusion independence (TI) across a broad range of heavily RBC TD ESA relapsed/refractory non-del(5q) LR-MDS patients (pts) naive to lenalidomide and hypomethylating agents (len/HMA). Aims: Evaluate the efficacy and safety of imetelstat vs placebo in this pt population in IMerge Phase 3. Methods: Heavily RBC TD ESA relapsed/refractory/ineligible (R/R) non-del(5q) LR-MDS pts naive to len/HMA were randomized 2:1 to receive imetelstat 7.5 mg/kg (N=118) or placebo (N=60) every 4 wks. The primary endpoint was 8-wk TI rate; subgroup analyses included IPSS risk, prior transfusion burden, and ring sideroblasts (RS) status. Secondary endpoints included 24-wk TI rate, TI duration, and hematologic improvement-erythroid (HI-E) rate. Change in mutation burden (variant allele frequency [VAF]) was exploratory. The primary analysis cutoff was Oct 2022; cutoff for ≥1-yr TI was Jan 2023. The primary and key secondary endpoints were compared using a Cochran-Mantel-Haenszel test stratified by prior transfusion burden and IPSS category. TI duration was calculated by Kaplan-Meier method and compared by stratified log-rank test. Results: The primary endpoint was met; 47 pts (39.8%) vs 9 pts (15.0%) receiving imetelstat vs placebo achieved 8-wk TI, P < 0.001. The rate of 8-wk TI was also significantly higher with imetelstat vs placebo across subgroups, including in RS negative pts. Median TI duration (95% CI) was 51.6 (26.9–83.9) wks with imetelstat vs 13.3 (8.0–24.9) wks with placebo, P < 0.001. Twenty-four-wk TI was achieved in 33 pts (28.0%) vs 2 pts (3.3%) receiving imetelstat vs placebo, P < 0.001. With 3 months' additional follow-up, 21 pts (17.8%) on imetelstat vs 1 pt (1.7%) on placebo achieved ≥1-yr TI, P = 0.002, representing 63.6% of ≥24-wk TI imetelstat responders (Figure). HI-E rates (2018 IWG, emphasizing >16-wk response) were 42.4% with imetelstat vs 13.3% with placebo, P < 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P < 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. VAF reduction in 3 genes frequently mutated in MDS was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration in imetelstat-treated pts, P < 0.001. No new safety signals were identified in IMerge P3. The most common Grade 3/4 AEs with imetelstat were thrombocytopenia and neutropenia; similar rates of Grade ≥3 bleeding and infections were observed on imetelstat and placebo. Cytopenias with imetelstat were of short duration, and >80% resolved to Grade ≤2 within 4 wks. Summary/Conclusion: Imetelstat demonstrated statistically significant and clinically meaningful efficacy with robust 8-wk, 24-wk, and 1-yr TI rates and durable continuous TI. For this LR-MDS patient population, almost one fifth of imetelstat-treated pts achieved continuous TI for ≥1 yr, representing substantial relief from transfusion-associated complications. VAF reduction and its correlation to clinical endpoints, including durable TI, support imetelstat's disease-modifying potential. Safety results were consistent with prior reports. Imetelstat treatment provides significant clinical benefit to a heavily TD LR MDS pt population in need of novel therapy.Keywords: Therapy, Clinical trial, Myelodysplastic syndrome, Telomerase activity